Mineral and Electrolyte Disorders With SGLT2i Therapy

Cianciolo, Giuseppe; Pascalis, Antonio De; Capelli, Irene; Gasperoni, Lorenzo; Lullo, Luca Di; Bellasi, Antonio; Manna, Gaetano La

doi:10.1002/jbm4.10242

Cited by 33 publications

(31 citation statements)

References 61 publications

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“…Glucagon reduces magnesium reabsorption in the proximal tubule, but strongly increases magnesium reabsorption in the thick ascending limb and distal convoluted tubule [16]. Furthermore, plasma insulin may cause a redistribution of magnesium from the extracellular to the intracellular compartment [17]. The increased plasma magnesium concentration upon SGLT2 inhibition could thus be caused by the increase in glucagon/insulin ratios [18].…”

Section: Discussionmentioning

confidence: 99%

SGLT2 inhibition versus sulfonylurea treatment effects on electrolyte and acid–base balance: secondary analysis of a clinical trial reaching glycemic equipoise: Tubular effects of SGLT2 inhibition in Type 2 diabetes

et al. 2020

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Sodium–glucose transporter (SGLT)2 inhibitors increase plasma magnesium and plasma phosphate and may cause ketoacidosis, but the contribution of improved glycemic control to these observations as well as effects on other electrolytes and acid–base parameters remain unknown. Therefore, our objective was to compare the effects of SGLT2 inhibitors dapagliflozin and sulfonylurea gliclazide on plasma electrolytes, urinary electrolyte excretion, and acid–base balance in people with Type 2 diabetes (T2D). We assessed the effects of dapagliflozin and gliclazide treatment on plasma electrolytes and bicarbonate, 24-hour urinary pH and excretions of electrolytes, ammonium, citrate, and sulfate in 44 metformin-treated people with T2D and preserved kidney function. Compared with gliclazide, dapagliflozin increased plasma chloride by 1.4 mmol/l (95% CI 0.4–2.4), plasma magnesium by 0.03 mmol/l (95% CI 0.01–0.06), and plasma sulfate by 0.02 mmol/l (95% CI 0.01–0.04). Compared with baseline, dapagliflozin also significantly increased plasma phosphate, but the same trend was observed with gliclazide. From baseline to week 12, dapagliflozin increased the urinary excretion of citrate by 0.93 ± 1.72 mmol/day, acetoacetate by 48 μmol/day (IQR 17–138), and β-hydroxybutyrate by 59 μmol/day (IQR 0–336), without disturbing acid–base balance. In conclusion, dapagliflozin increases plasma magnesium, chloride, and sulfate compared with gliclazide, while reaching similar glucose-lowering in people with T2D. Dapagliflozin also increases urinary ketone excretion without changing acid–base balance. Therefore, the increase in urinary citrate excretion by dapagliflozin may reflect an effect on cellular metabolism including the tricarboxylic acid cycle. This potentially contributes to kidney protection.

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Section: Discussionmentioning

confidence: 99%

SGLT2 inhibition versus sulfonylurea treatment effects on electrolyte and acid–base balance: secondary analysis of a clinical trial reaching glycemic equipoise: Tubular effects of SGLT2 inhibition in Type 2 diabetes

et al. 2020

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“…Moreover, interestingly, increased sodium has been shown to promote inflammatory cytokines and inhibit anti-inflammatory function of innate and adaptative immune cells. Inflammatory cytokines such as interleukin 6 [22], interleukin 1 [22], interferon-γ [23] and tumor necrosis factor α (TNFα) can affect sodium handling through changes in the expression of renal sodium transporters, renin angiotensin aldosterone system(RAAS) and nitric oxide [24] bioavailability [25]. IFN-γ positively regulates sodium/hydrogen exchanger 3 (NHE3) in the proximal tubule and NKCC2 and the sodium chloride co-transporter (NCC) in the distal tubule.…”

Section: Sglt2i Sodium and Inflammatory Cytokinesmentioning

confidence: 99%

“…Moreover, interestingly, increased sodium has been shown to promote inflammatory cytokines and inhibit anti-inflammatory function of innate and adaptative immune cells. The complex interplay at renal tubule between sodium, tubular transporters, and inflammatory cytokines [22][23][24]. Abbreviations: AGT, angiotensinogen; ATI, angiotensin I; ATII, angiotensin II; ACE, angiotensin-converting enzyme; NHE3, sodium/hydrogen exchanger 3; IFN-γ, interferon-γ; IL-6, interleukin-6; NKCC2, sodium-potassium-two chloride cotransporter; NCC, sodium-chloride cotransporter; ENaC, epithelial sodium channel; IL-1, interleukin-1.…”

Section: Sglt2i Sodium and Inflammatory Cytokinesmentioning

confidence: 99%

“…Although data are still not conclusive, it is important to emphasize that a growing body of evidence suggests that the use of SGLT2i may have some effects on bone health and the mineral metabolism index [24]. Increased bone fragility and risk of fracture are features of both type 1 diabetes and T2D, and may be caused by poor bone quality and abnormal bone microarchitecture [56].…”

Section: Effect Of Sglt2i On Calcium and Phosphate Homeostasismentioning

confidence: 99%

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The Off-Target Effects, Electrolyte and Mineral Disorders of SGLT2i

et al. 2020

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The sodium-glucose cotransporter 2 inhibitors (SGLT2i) are a relatively new class of antidiabetic drugs that, in addition to emerging as an effective hypoglycemic treatment, have been shown to improve, in several trials, both renal and cardiovascular outcomes. In consideration of the renal site of action and the associated osmotic diuresis, a negative sodium balance has been postulated during SGLT2i administration. Although it is presumable that sodium and water depletion may contribute to some positive actions of SGLT2i, evidence is far from being conclusive and the real physiologic effects of SGLT2i on sodium remain largely unknown. Indeed, no study has yet investigated how SGLT2i change sodium balance in the long term and especially the pathways through which the natriuretic effect is expressed. Furthermore, recently, several experimental studies have identified different pathways, not directly linked to tubular sodium handling, which could contribute to the renal and cardiovascular benefits associated with SGLT2i. These compounds may also modulate urinary chloride, potassium, magnesium, phosphate, and calcium excretion. Some changes in electrolyte homeostasis are transient, whereas others may persist, suggesting that the administration of SGLT2i may affect mineral and electrolyte balances in exposed subjects. This paper will review the evidence of SGLT2i action on sodium transporters, their off-target effects and their potential role on kidney protection as well as their influence on electrolytes and mineral homeostasis.

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“…Although current evidence supports their safety, additional efforts are needed to elucidate the long-term impact of these compounds on chronic kidney disease, mineral metabolism, and bone health. Indeed, the limited study follow-up precludes a definitive answer on the impact of gliflozins (e.g., on electrolyte and mineral metabolism changes), especially in high-risk subgroups of patients [9]. The findings of ongoing and future clinical trials will help shed further light on the role of gliflozins in the long-term protection of renal function.…”

Section: Introductionmentioning

confidence: 99%

No Cytotoxic and Inflammatory Effects of Empagliflozin and Dapagliflozin on Primary Renal Proximal Tubular Epithelial Cells under Diabetic Conditions In Vitro

Baer

Koch

Freitag

et al. 2020

IJMS

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Gliflozins are inhibitors of the renal proximal tubular sodium-glucose co-transporter-2 (SGLT-2), that inhibit reabsorption of urinary glucose and they are able to reduce hyperglycemia in patients with type 2 diabetes. A renoprotective function of gliflozins has been proven in diabetic nephropathy, but harmful side effects on the kidney have also been described. In the current project, primary highly purified human renal proximal tubular epithelial cells (PTCs) have been shown to express functional SGLT-2, and were used as an in vitro model to study possible cellular damage induced by two therapeutically used gliflozins: empagliflozin and dapagliflozin. Cell viability, proliferation, and cytotoxicity assays revealed that neither empagliflozin nor dapagliflozin induce effects in PTCs cultured in a hyperglycemic environment, or in co-medication with ramipril or hydro-chloro-thiazide. Oxidative stress was significantly lowered by dapagliflozin but not by empagliflozin. No effect of either inhibitor could be detected on mRNA and protein expression of the pro-inflammatory cytokine interleukin-6 and the renal injury markers KIM-1 and NGAL. In conclusion, empa- and dapagliflozin in therapeutic concentrations were shown to induce no direct cell injury in cultured primary renal PTCs in hyperglycemic conditions.

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Mineral and Electrolyte Disorders With SGLT2i Therapy

Cited by 33 publications

References 61 publications

SGLT2 inhibition versus sulfonylurea treatment effects on electrolyte and acid–base balance: secondary analysis of a clinical trial reaching glycemic equipoise: Tubular effects of SGLT2 inhibition in Type 2 diabetes

SGLT2 inhibition versus sulfonylurea treatment effects on electrolyte and acid–base balance: secondary analysis of a clinical trial reaching glycemic equipoise: Tubular effects of SGLT2 inhibition in Type 2 diabetes

The Off-Target Effects, Electrolyte and Mineral Disorders of SGLT2i

No Cytotoxic and Inflammatory Effects of Empagliflozin and Dapagliflozin on Primary Renal Proximal Tubular Epithelial Cells under Diabetic Conditions In Vitro

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